Metabolic Phenotyping of an Adoptive Transfer Mouse Model of Experimental Colitis and Impact of Dietary Fish Oil Intake

Inflammatory bowel diseases are acute and chronic disabling inflammatory disorders with multiple complex etiologies that are not well-defined. Chronic intestinal inflammation has been linked to an energy-deficient state of gut epithelium with alterations in oxidative metabolism. Plasma-, urine-, stool-, and liver-specific metabonomic analyses are reported in a naïve T cell adoptive transfer (AT) experimental model of colitis, which evaluated the impact of long-chain n-3 polyunsaturated fatty acid (PUFA)-enriched diet. Metabolic profiles of AT animals and their controls under chow diet or fish oil supplementation were compared to describe the (i) consequences of inflammatory processes and (ii) the differential impact of n-3 fatty acids. Inflammation was associated with higher glycoprotein levels (related to acute-phase response) and remodeling of PUFAs. Low triglyceride levels and enhanced PUFA levels in the liver suggest activation of lipolytic pathways that could lead to the observed increase of phospholipids in the liver (including plasmalogens and sphingomyelins). In parallel, the increase in stool excretion of most amino acids may indicate a protein-losing enteropathy. Fecal content of glutamine was lower in AT mice, a feature exacerbated under fish oil intervention that may reflect a functional relationship between intestinal inflammatory status and glutamine metabolism. The decrease in Krebs cycle intermediates in urine (succinate, α-ketoglutarate) also suggests a reduction in the glutaminolytic pathway at a systemic level. Our data indicate that inflammatory status is related to this overall loss of energy homeostasis

Specific Dietary Preferences Are Linked to Differing Gut Microbial Metabolic Activity in Response to Dark Chocolate Intake

Systems biology approaches are providing novel insights into the role of nutrition for the management of health and disease. In the present study, we investigated if dietary preference for dark chocolate in healthy subjects may lead to different metabolic response to daily chocolate consumption. Using NMR- and MS-based metabolic profiling of blood plasma and urine, we monitored the metabolic response of 10 participants stratified as chocolate desiring and eating regularly dark chocolate (CD) and 10 participants stratified as chocolate indifferent and eating rarely dark chocolate (CI) to a daily consumption of 50 g of dark chocolate as part of a standardized diet over a one week period. We demonstrated that preference for chocolate leads to different metabolic response to chocolate consumption. Daily intake of dark chocolate significantly increased HDL cholesterol by 6% and decreased polyunsaturated acyl ether phospholipids. Dark chocolate intake could also induce an improvement in the metabolism of long chain fatty acid, as noted by a compositional change in plasma fatty acyl carnitines. Moreover, a relationship between regular long-term dietary exposure to a small amount of dark chocolate, gut microbiota, and phenolics was highlighted, providing novel insights into biological processes associated with cocoa bioactives

Bar plots describing metabolite variations in the study population stratified in four quartiles according to visceral fat adiposity (intraperitoneal fat) at V2.

<p>Statistical significance is reported in Table S3. Key: PC-O, 1-O-alkyl-2- acylglycerophosphocholines. Assignment of PC-O species is made on the assumption that only even numbered carbon chains are present. A potential overlap between PC species containing odd-chain fatty acids and even-chained PC-O species cannot be excluded with low mass resolution.</p

Statistically significant Spearman correlation map between body fat composition parameters and clinical measures (95% confidence interval).

<p>Log₁₀ values of IPVF, VAT/SAT, VAT/total abdominal fat were strongly associated with HOMA-IR (r = 0.39, p = 0.015; r = 0.56, p<0.001; r = 0.55, p<0.001) and fasting insulin (r = 0.35, p = 0.0275; r = 0.49, p = 0.0017; r = 0.48, p = 0.0020). Strong associations were observed with ALAT (r = 0.39, p = 0.0128; r = 0.37, p = 0.0175; r = 0.38, p = 0.0167) and ALAT/ASAT ratio (r = 0.44, p = 0.0044; r = 0.35, p = 0.0268; r = 0.35, p = 0.0302). IPVF and Log₁₀ values of IPVF correlated with waist (r = 0.55, p<0.001; r = 0.35, p = 0.04) and waist/hip ratio (r = 0.69, p<0.001; r = 0.52, p = 0.0017), but not Log₁₀ values of VAT/SAT and VAT/total abdominal fat. NB: Blue denotes negative correlation, orange denotes positive correlation, and black denotes no correlation.</p

Plot describing metabolite importance and robustness in predicting visceral fat adiposity as assessed by Random forest analysis using metabolic data collected at V0 and V2.

<p>Visceral adiposity was associated with increasing concentrations of amino acids (glutamine, leucine/isoleucine, phenylalanine and tyrosine), lysophosphatidylcholine LPC 24∶0 and diacyl phospholipids (PC 30∶0, PC 34∶4). In addition, visceral adiposity was marked by a depletion in ether lipid species PC<i>-O</i> 36∶3, PC<i>-O</i> 40∶3, PC<i>-O</i> 40∶4, PC<i>-O</i> 40∶6, PC<i>-O</i> 42∶2, PC<i>-O</i> 42∶3, PC<i>-O</i> 42∶4, PC<i>-O</i> 44∶3, PC<i>-O</i> 44∶4, PC<i>-O</i> 44∶6, and two diacyl phosphocholines (PC 42∶0 and PC 42∶2). To reflect the weight of the selected biomarkers in the classification of visceral adiposity, a pooled mean decrease of accuracy for each compound was calculated from 10000 forest generations. Higher variable importance corresponds to higher values of pooled mean decrease in accuracy. Key: IPVF, intraperitoneal fat volume; LPC, Lysophosphatidylcholines; PC, Phosphatidylcholines; PC-O, 1-O-alkyl-2- acylglycerophosphocholines; Ratio1, intraperitoneal/subcutaneous fat ratio; Ratio 2, intraperitoneal/abdominal fat ratio. Assignment of PC-O species is made on the assumption that only even numbered carbon chains are present. A potential overlap between PC species containing odd-chain fatty acids and even-chained PC-O species cannot be excluded with low mass resolution.</p

Metabolite variations across subjects stratified according to intraperitoneal/abdominal fat ratio.

<p>NB: Blood plasma metabolites highlighted by multivariate analyses are reported as mean values ± SD. Key: Qi: data for population quartile i according to intraperitoneal/abdominal fat ratio. 12-HETE, 12-hydroxy-eicosatetraenoic acid; 15-HETE, 12-hydroxy-eicosatetraenoic acid; 9-HODE, 9-Hydroxy-10,12-octadecadienoic acid; AA, arachidonic acid; LPC, Lysophosphatidylcholines; PC, Phosphatidylcholines; PC-O, 1-O-alkyl-2- acylglycerophosphocholines; SM, Sphingomyelines; SM-OH, Hydroxy-Sphingomyelin.</p>*<p>Assignment of PC-O species is made on the assumption that only even numbered carbon chains are present. A potential overlap between PC species containing odd-chain fatty acids and even-chained PC-O species cannot be excluded with low mass resolution.</p

Descriptive statistics of subjects stratified according to intraperitoneal/abdominal fat ratio.

<p>Key: Qi: data for population quartile i according to intraperitoneal/abdominal fat ratio. BMI = body mass index, HDL-C =  high density lipoprotein cholesterol, homeostasis model assessment of insulin resistance =  HOMA-IR, LDL-C =  low density lipoprotein cholesterol, TG =  triglycerides, MAP =  mean arterial blood pressure, ALAT =  alanine aminotransferase, ASAT =  aspartate aminotransferase, GGT =  gamma-glutamyl transpeptidase, NEFAs = non esterified fatty acids. Data are reported as mean values ± SD.</p

Insulin and glucose response to oral glucose tolerance test according to intraperitoneal/abdominal fat ratio.

<p>NB: Values are reported as mean values ± SD. Key: Qi: data for population quartile i according to intraperitoneal/abdominal fat ratio.</p